Ophthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis

doi:10.1016/j.ophtha.2012.12.040

Ophthalmology

Volume 120, Issue 7, July 2013, Pages 1432-1439

Poster presented at: the American Academy of Ophthalmology Annual Meeting, October 23, 2011, Orlando, Florida.

https://doi.org/10.1016/j.ophtha.2012.12.040 Get rights and content

Purpose

To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS).

Design

Analysis done on pooled safety data (N = 2615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension >5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies).

Participants

Patients aged 18 to 55 years (18–60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or macular edema (ME) at screening were excluded.

Intervention

Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA).

Main Outcome Measures

Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board.

Results

Among 2615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3%; 1.25 mg: n = 15, 1.2%). Most patients (n = 13, 68%) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68%); 2 patients had late onset (>12 months) ME. Of the 19 patients with ME, 5 (26%), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1%) in the all studies group. In most cases (n = 16, 84%), ME resolved after discontinuing the study drug. Eleven patients required topical anti-inflammatory medications. No patient had further vision deterioration.

Conclusions

Fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Population

Analyses were based on pooled data from the phase 2 and 3 core and extension studies for MS (N = 2615, “all studies group” safety population, patients who received at least 1 dose of fingolimod). The phase 2 core study (FTY720D2201) of 6 months' duration was a double-masked, randomized, placebo-controlled study⁹ and had an optional long-term extension phase¹⁰ of more than 5 years. FREEDOMS⁵ (FTY720D2301; FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) was a

Results

Patient disposition and incidence of ME in the MS clinical studies of fingolimod are shown in Figure 2 (available at http://aaojournal.org).

Among 2615 patients of the all studies group safety population assessed in this pooled analysis, 19 cases of ME were confirmed by the retina specialist on the DSMB. Among 1176 patients who received fingolimod 0.5 mg, 4 (0.3%) developed ME, and among the 1302 patients who received fingolimod 1.25 mg, 15 (1.2%) developed ME. Macular edema occurred in both

Discussion

Macular edema is an important cause of central vision loss and is associated with a serious impact on the social and economic aspects of an individual's life.¹¹ Beyond the direct impact on vision, and thus disability, it has also been found that patients with MS and ME can have significantly worse disability (as measured by the Expanded Disability Status Scale¹²) and rate of disease progression (as measured by the MS Severity Scale¹³) than those without ME.¹⁴ The cause and pathophysiology of ME

Acknowledgments

The authors thank Uma Kundu and Hashem Salloukh (Medical Communications, Novartis Healthcare Pvt. Ltd.) for providing medical writing support. This encompassed preparing the first draft, checking content and language, formatting, referencing, preparing tables and figures, incorporating the authors' revisions, and submission, all under the direction of the authors.

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The selective sphingosine 1-phosphate receptor (S1P_1,5) modulator siponimod has largely replaced the older and non-selective fingolimod as a treatment for relapsing multiple sclerosis due to its improved side effect profile. Initial clinical trials demonstrated no cases of macular edema in patients taking siponimod, but several cases were later noted in the EXPAND trial.
Here, we report the case of a 54-year-old woman with MS on siponimod who developed macular edema three months after initiating treatment that resolved with cessation of siponimod and use of topical anti-inflammatory therapy.
Neurologists should be aware that like fingolimod, Siponimod can cause macular edema, particularly in those with a history of diabetes and uveitis. Physicians should therefore consider sending their high-risk patients for eye exams within 4 months of initiating treatment.
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The sphingolipids ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine (Sph), and sphingosine-1-phosphate (S1P)) are key signaling molecules that regulate many patho-biological processes. During the last decade, they have gained increasing attention since they may participate in important and numerous retinal processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Cer for instance has emerged as a key mediator of inflammation and death of neuronal and retinal pigment epithelium cells in experimental models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. S1P may have opposite biological actions, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1- phosphate may also contribute to uveitis. Furthermore, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), have been shown to preserve neuronal viability and retinal function. Collectively, the expanding role for these sphingolipids in the modulation of vital processes in retina cell types and in their dysregulation in retinal degenerations makes them attractive therapeutic targets.
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To explore prospectively through OCT the rate of retinal layer changes in relapsing-remitting multiple sclerosis patients followed up on fingolimod or interferon, as well as the treatments’ differential effects on cognitive tests scores.
This prospective observational study enrolled 128 stable RRMS patients treated either with fingolimod (n = 71) or interferon (n = 56). Symbol-Digit Modality Test and retinal OCT scans were obtained at baseline and every 6 to 12 months. A subgroup of patients underwent expanded cognitive tests annually (Brief visual-spatial memory-total recall, BVMT-delayed recall, and Montreal Cognitive Assessment). Retinal-OCT scans were also obtained from 22 age- and sex-matched healthy controls. Mixed effects regression was used to study annualized changes in retinal layers and cognitive function, including differences between treatment groups. Correlations between annualized changes in retinal measurements and cognitive scores were also explored.
Fingolimod treated patients showed no significant difference in the rate of thinning of all retinal layers when compared to healthy controls and had significantly less GCIPL thinning when compared to interferons. SDMT scores improved similarly among both RRMS treatment groups. However, interferon but not fingolimod treated patients had significant decline in MOCA and total recall scores. We also found correlations between the annualized change in GCIPL thickness and annualized change in MOCA scores, and similar correlations with annualized change in total recall scores.
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The sphingosine 1-phosphate (S1P) receptor 1 (S1P₁) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P₁ that has been approved for oral treatment of MS. Previously, we have developed novel butterfly derivatives of FTY720 that acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE).
In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterised their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H₃R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H₃R affinities, and in addition, ST-1505 was characterised as a dual S1P₁₊₃ agonist, whereas ST-1478 was a dual S1P₁₊₅ agonist. Both multitargeting compounds were also active in mice and reduced the lymphocyte numbers as well as diminished disease symptoms in the mouse model of MS. The effect of ST-1478 was dependent on SK-2 activity suggesting that it is a prodrug like FTY720, but with a more selective S1P receptor activation profile, whereas ST-1505 is a fully active drug even in the absence of SK-2.
In summary, these data suggest that the well soluble piperidine derivatives ST-1505 and ST-1478 hold promise as novel drugs for the treatment of MS and other autoimmune or inflammatory diseases, and by their H₃R antagonist potency, they might additionally improve cognitive impairment during disease.
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Acute optic neuritis is the most common neuro-opthalmologic manifestation of multiple sclerosis (MS). Treatment with high-dose intravenous corticosteroids accelerates visual recovery, although it has no long-term visual benefit. MS has several others, less common, neuro-ophthalmological manifestations, where corticotherapy may not be the best treatment option. Neuro-ophthalmologic manifestations of MS other than optic neuritis can be divided in afferent and efferent visual pathways, acute and chronic and may be associated with drugs that are employed in MS. The authors propose is to review the neuro-ophthalmologic manifestations of multiple sclerosis other than optic neuritis. Recognition of these leads to a more targeted treatment and may prevent visual deterioration.

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: Manuscript no. 2012-873.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): M.A.Z. is a consultant for Novartis Pharma AG (Basel, Switzerland); L.M.J. was a former consultant for Novartis Pharma AG (Basel, Switzerland); R.D.J. is a consultant for Novartis Pharma AG (Basel, Switzerland); A.T.R. is a consultant for Novartis Pharma AG (Basel, Switzerland); G.F. is a full-time employee of Novartis Pharmaceuticals Corporation (East Hanover, NJ); W.C. is a full-time employee of Novartis Pharma AG (Basel, Switzerland); D.T. is a full-time employee of Novartis Pharmaceuticals Corporation (East Hanover, NJ); and X.J. is a full-time employee of Novartis Pharmaceuticals Corporation (East Hanover, NJ). At all stages the authors have had control over the content of this manuscript, for which they have given final approval and take full responsibility. Novartis Pharma AG enforces a “no ghostwriting” policy. As funding sponsors, they have had the opportunity to review the manuscript but do not have the authority to change any aspect of the manuscript.

: Funding: The studies were funded by Novartis Pharma AG (Basel, Switzerland) and are registered with Clinicaltrials.gov (Phase 2 core: NCT00333138; Phase 2 extension study: NCT00235430; FREEDOMS and extension study: NCT00289978; TRANSFORMS and extension study: NCT00340834). The sponsor participated in the design of the study, conducting the study, data collection, data management, and data analysis, interpretation of the data, preparation, and review and approval of the manuscript. Supported in part by unrestricted grants from the Research to Prevent Blindness, Inc. (New Jersey Medical School, Northwestern University), the Eye Institute of New Jersey, and the NJ Lions Eye Research Foundation.

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Original articleOphthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis

Purpose

Design

Participants

Intervention

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Study Population

Results

Discussion

Acknowledgments

Am J Transplant

Pharmacol Ther

Curr Opin Pharmacol

J Biol Chem

Lancet Neurol

Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis

Clin Neuropharmacol

FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system

Br J Pharmacol

FDA approves first oral drug to reduce MS relapses [press release]

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis

N Engl J Med

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis

N Engl J Med

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation

Transplantation

FTY720 (fingolimod) in renal transplantation

Clin Transplant

Oral fingolimod (FTY720) for relapsing multiple sclerosis

N Engl J Med

Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study

Neurology

Multiple sclerosis associated with uveitis in two large clinic-based series

Neurology

Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS)

Neurology

Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity

Neurology

Original article
Ophthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis